HZ is a disease caused by varicella-zoster virus (hereinafter referred to as VZV for short). About 95% of people experience primary infection with VZV in their childhood and acquire life-long immunity after cure. However, VZV itself, after the infection, is carried latent in sensory ganglions all over the body. While most people manifest no symptoms even after VZV having becoming latent, some people allow reactivation and propagation of VZV hidden in ganglions due to weakened responses in their immunologic mechanism and, whereby vesicles and neuralgia are manifested in the nerve field invariably unilaterally and zonally.
HZ as a result of this reactivation of VZV occurs in several parts simultaneously mainly on the chest and/or face. Eruption subsides, on an average, in about 3 weeks and neuralgia gradually abates in 1 to 3 months. And, in the aged, intractable neuralgia called PHN may remain or recur, causing troubles in everyday life, such as insomnia. The pain caused by VZV includes acute stage (HZ) pain and PHN, among which PHN, in particular, has been very difficult to treat effectively.
In cases where the pain due to HZ is slight, oral administration of an NSAID (nonsteroidal anti-inflammatory drug) is effective as the case may be, whereas, in the case of severe pain, it is necessary to perform nerve block. In the case of PHN, it is difficult to produce analgesic effects on severe pains in old cases having a history of 1 year or longer even by means of nerve block. Generally, administration of an NSAID is ineffective and, although oral administration of a tricyclic antidepressant or clonidine, iontophoresis with lidocaine, application of a 0.075% capsaicin ointment, a 2% aspirin ointment or a lidocaine ointment and use of an indomethacine patch and so forth have been attempted, there is almost no effective key therapeutic method available at present.
The local anesthetic effect of lidocaine is well known, and lidocaine has already been used in nerve block or iontophoresis as a treatment to alleviate the pain of HZ and PHN. These methods, however, require patients to receive regular outpatient treatment and often produce some problems, namely its anesthetic effect is unreliable and it causes anxiety about infection upon its injection or about electric shock. Therefore, the establishment of an effective therapeutic method has been desired which enables home treatment, gives no feeling of anxiety to patients and is free of the possibility of infection by frequent injections.
As a method for realizing such desire, a therapeutic method is conceivable which uses a medicinal means, such as an oral administration or an external administration, other than injection or dripping. Generally, however, as frequently reported for oral preparations, there are problems, for example long-term use may result in manifestation of side effects such as gastrointestinal disorder and the drug has to pass through the liver before arriving at the target site and therefore undergoes partial degradation in the liver (first pass effect). A further known drawback is that even if a side effect should have once been produced after administration, the drug can never be removed.
Therefore, various preparations suited for transdermal administration have been reported as dosage forms capable of removing these drawbacks. As external lidocaine preparations, ointments, jellies, sprays and the like have been marketed but, as far as skin surface anesthesia is concerned, satisfactory anesthetic effects have not been obtained as yet. Further, lidocaine gels as hospital preparations are sometimes used in the treatment of HZ and PHN but an ODT (occlusive dressing technique) is required after application. The development of an effective patch which can be used in a simple and easy manner has thus been desired. No such one has been marketed as yet.
Meanwhile, Japanese Patent Prepublication No. 02-300138 discloses a lidocaine-containing “composition characterized in that a long-term pain-alleviating effect is sustained after removal of the preparation”. However, as can be deduced from the mere description “the effect was evaluated at one-hour intervals following lidocaine application for 4 hours”, the preparation is expected only to be effective for about 4 hours at the longest. A preparation which is effective for a longer period of time is demanded.
On the other hand, Japanese Patent Prepublication No. 04-305523 discloses a patch for external use for the treatment of pain due to HZ and of PHN. This external patch is a preparation which comprises a water-soluble polymer, water and a water retaining agent as essential components and contains lidocaine or a salt thereof in the so-called aqueous poultice or cataplasm base. In this reference, moisture is said to be effective for improving the permeability of the drug. Since, in reality, however, lidocaine is scarcely soluble in water, addition of a large amount of lidocaine may result in precipitation of crystals in the water-soluble base, hence the alleged pharmacological effect is questionable. The use of a salt of lidocaine in lieu of lidocaine is also conceivable. While such a lidocaine salt itself is readily soluble in water, it is a substance hardly absorbable through the skin. The preparation disclosed in the reference cited above is thus evaluated as one that can hardly be said to be satisfactory from the viewpoint of actual drug absorption.
Further, the present inventors have already found out a patch having sustained pain-alleviating action characterized by that lidocaine as an active ingredient and an oleaginous component, as a release controlling agent, selected from the group consisting of liquid paraffins, higher fatty acids and vegetable oils are incorporated in an adhesive mass base comprising a styrene-isoprene-styrene block copolymer and a tackifier and the resulting mixture is supported on a flexible backing (Japanese Patent Prepublication No. 10-147521). The period over which the pain-alleviating effect of this preparation has been confirmed, however, is only 24 hours. A preparation capable of releasing a local anesthetic, such as lidocaine, over a longer period of time is thus demanded.
For obtaining a transdermal preparation having good application characteristics, it is a matter of course that its efficacy and safety should have been confirmed and, in addition, it should have those characteristics which are fundamental to transdermal preparations and typical of patches. Thus, for instance, it should adhere to the skin well, should not cause abrasion of the stratum corneum upon peeling thereof, and should not give pain upon peeling thereof. In particular, the pain due to the diseases in question lasts long in many cases, hence repeated administrations to the painful site or sites on the skin is anticipated; therefore, it is required that the abrasion of the stratum corneum, which is causative of skin irritation, be slight. Thus, for preparing a practical transdermal preparation, it is necessary to select the adhesion, keying, cohesion and other parameters in a manner such that they are well balanced among them. In the actual circumstances, however, it can hardly be said that a transdermal preparation having fully satisfactory characteristics has so far been provided.
Thus, under the circumstances in which it can hardly be said that a practical patch suited for alleviating lasting pains, such as the pain due to HZ or PHN, is at present available, the development of a transdermal preparation more improved in efficacy, safety and application characteristics is required.